Global and Local Regulation of Neuronal Differentiation by Calcium Transients

Abstract

Embryonic spinal neurons express ion channels prior to synaptogenesis that mediate specialized forms of excitability promoting Ca ²⁺ influx. Ca ²⁺ imaging has revealed that these cells generate three distinct types of elevations of intracellular Ca ²⁺, which appear to encode developmental information in the frequency with which they are produced. Ca ²⁺ spikes (∼ 10 s duration) are generated by Ca ²⁺-dependent action potentials and Ca ²⁺-induced Ca ²⁺-release and transcriptionally regulate the developmental appearance of GABA in cultured neurons. Growth cone Ca ²⁺ transients (˜30 s duration) are generated by influx and release from stores and regulate the rate of axon outgrowth both in vivo and in cultured neurons. They inhibit axon extension through activation of the Ca ²⁺-dependent phosphatase, calcineurin (CN), that affects the actin cytoskeleton. Filopodial Ca ²⁺ transients (˜0.3 s duration) are generated by influx through Ca ²⁺ channels activated by integrin receptors in cultured neurons. They promote turning when asymmetrically generated at a substrate border or when artificially imposed in selected filopodia, by activation of the Ca ²⁺-dependent protease calpain. Developmental regulation by Ca ²⁺ transients provides function-dependent feedback that may compensate for variation in gene expression and facilitate regulation by environmental stimuli.